Astrocytic Nrf2 modulates microglial phagocytosis in environmental pollution-induced depressive-like mice

Abstract Long-term air pollution has been associated with depression in population; however, the underlying mechanism remains largely unknown. Here, we show that in the context of ambient fine particulate matter (PM2.5) exposure, mice display depressive-like behaviors, accompanied with neurotoxic activation (A1 polarization) and disturbed redox balance of astrocytes. Enhanced Nrf2 expression protected astrocytes from A1 polarization. Evidenced by bilateral and unilateral astrocytic Nrf2 knockdown (KD) murine models, it was found that loss of Nrf2 in astrocytes decreased the expression of cytokines mediating astrocyte-to-microglia communication, and thereby disrupted phagocytotic ability of microglia, which eventually aggravates the depression-like behaviors in mice. Moreover, supplement of a phytochemical, procyanidin (PC), mimics the function of Nrf2 agonist, is beneficial to ameliorate the depressive-like behaviors in PM2.5-exposed mice. These results suggest that Nrf2 plays an essential role to maintain the astrocyte-to-microglia communication and redox balance in hippocampus, and effectively protects mice against depressive-like behaviors during PM2.5 exposure.